Stochastic resonance induced by a multiplicative periodic signal in the gene transcriptional regulatory system with correlated noises

This paper investigates the stochastic resonance (SR) induced by a multiplicative periodic signal in the gene transcriptional regulatory system with correlated noises.The expression of the signal-to-noise ratio (SNR) is derived.The results indicate that the existence of a maximum in SNR vs.the additive noise intensity α,the multiplicative noise intensity D and the cross-correlated noise intensity λ is the identifying characteristic of the SR phenomenon and there is a critical phenomenon in the SNR as a function of λ,i.e.,for the case of smaller values of noise intensity (α or D),the SNR decreases as λ increases;however,for the case of larger values of noise intensity (α or D),the SNR increases as λ increases.

Distinct regulatory mechanism of immunoglobulin gene transcription in epithelial cancer cells

The restriction of immunoglobulin(Ig)expression to B lymphocytes is well established.However,several reports have confirmed that the Ig gene can be expressed in many non-B cancer cells and/or some normal cells.Our aim is to determine whether the Ig gene promoter can be activated in non-B cancer cells and to identify the regulatory mechanism for Ig gene expression.Our results show that the Ig promoter of VH4-59 was activated in several non-B cancer cell lines.Moreover,two novel positive regulatory elements,an enhancer-like element at 2800 to 2610 bp and a copromoter-like element at 2610 to 2300 bp,were identified in two epithelial cancer cell lines,HeLa S3 and HT-29.The octamer element(59-ATGCAAAT-39)located in the Ig promoter,a crucial element for B-cell-derived Ig gene transcription,was also very important for non-B-cell-derived Ig gene transcription.More importantly,we confirmed that octamer-related protein-1(Oct-1),but not Oct-2,was a crucial transcriptional factor for Ig gene transcription due to its ability to bind to the octamer element of the Ig promoter in epithelial cancer cells.These results suggested the presence of a distinct regulatory mechanism for Ig gene expression in non-B cancer cells.

The RNF20/40 complex regulates p53-dependent gene transcription and mRNA splicing

p53 is a key transcription factor to regulate gene transcription.However,the molecular mechanism of chromatin-associated p53 on gene transcription remains elusive.Here,using unbiased protein affinity purification,we found that the RNF20/40 complex associated with p53 on the chromatin.Further analyses indicated that p53 mediated the recruitment of the RNF20/40 complex to p53 target gene loci including p21 and PUMA loci and regulated the transcription of p21 and PUMA via the RNF20/40 complex-dependent histone H2B ubiquitination(ubH2B).Lacking the RNF20/40 complex suppressed not only ubH2B but also the generation of the mature mRNA of p21 and PUMA.Moreover,ubH2B was recognized by the ubiquitin-binding motif of pre-mRNA processing splicing factor 8(PRPF8),a subunit in the spliceosome,and PRPF8 was required for the maturation of the mRNA of p21 and PUMA.Our study unveils a novel p53-dependent pathway that regulates mRNA splicing for tumor suppression.

Changes in the Photosynthetic Pigment Contents and Transcription Levels of Phycoerythrin-Related Genes in Three Gracilariopsis lemaneiformis Strains Under Different Light Intensities

Three Gracilariopsis lemaneiformis strains,including wild type and high-temperature-resistant cultivars 981 and 2007,were studied with the changes in their photosynthetic pigment contents and related gene transcription levels under different light intensities(10,60,100,and 200μmolm^(−2)s^(−1)).The three G.lemaneiformis strains had the following photosynthetic pigments with high-to-low contents:phycoerythrin(PE),phycocyanin(PC),allophycocyanin(APC),and chlorophyll a(Chl a).Among the three strains,cultivar 981 had the highest PE content,followed by cultivar 2007.The PC and APC contents were similar among the three strains,but they were higher in cultivars 981 and 2007 than in the wild type.The Chl a contents in the three G.lemaneiformis strains were equal.A low light intensity(10μmolm^(−2)s^(−1))promoted photosynthetic pigment accumulation in G.lemaneiformis and improved the relative PE gene transcription(peA and peB)in a short period(≤6 d).A high light intensity decreased the PE content.PebA and PebB,which catalyzed phycoerythrobilin synthesis,showed no compensatory upregulation at a low light intensity among the strains except for the wild type.At a high light intensity,transcription levels of pebA and pebB in the three strains were upregulated.This study provided an experimental basis for elucidating the photosynthesis of G.lemaneiformis.As key genes of algal growth,photo-synthesis-related genes served as useful gene markers for screening elite varieties with good traits in breeding.Cultivar 2007 was superior to cultivar 981 in terms of maintaining high pigment levels in a wide range of light intensities,which is the most suitable for aquaculture.

Genome-wide analyses on transcription factors and their potential microRNA regulators involved in maize male fertility

Anther development is a programmed biological process crucial to plant male reproduction. Genomewide analyses on the functions of transcriptional factor(TF) genes and their microRNA(miRNA) regulators contributing to anther development have not been comprehensively performed in maize. Here, using published RNA-Seq and small RNA-Seq(sRNA-Seq) data from maize anthers at ten developmental stages in three genic male-sterility(GMS) mutants(ocl4, mac1, and ms23) and wild type W23, as well as newly sequenced maize anther transcriptomes of ms7-6007 and lob30 GMS mutants and their WT lines, we analyzed and found 1079 stage-differentially expressed(stage-DE) TF genes that can be grouped into six(premeiotic, meiotic, postmeiotic, premeiotic-meiotic, premeiotic-postmeiotic, and meiotic-postmeiotic clusters) expression clusters. Functional enrichment combined with cytological and physiological analyses revealed specific functions of genes in each expression cluster. In addition, 118 stage-DE miRNAs and99 miRNA-TF gene pairs were identified in maize anthers. Further analyses revealed the regulatory roles of zma-miR319 and zma-miR159 as well as ZmMs7 and ZmLOB30 on ZmGAMYB expression. Moreover,ZmGAMYB and its paralog ZmGAMYB-2 were demonstrated as novel maize GMS genes by CRISPR/Cas9 knockout analysis. These results extend our understanding on the functions of miRNA-TF gene regulatory pairs and GMS TF genes contributing to male fertility in plants.

Personalized Management of Chronic Myeloid Leukemia Presenting with Ovarian Apoplexy and Review of Health Emergency Cases

Introduction: Chronic myeloid leukemia (CML) may significantly affect quality of life and life expectancy in the accelerated and acute phases, especially if presented with health emergencies. Objective: The purpose of the study was the evaluation of the personalized management milestones in CML cases presented with ovarian apoplexy and the analysis of the international experience on health emergencies in this leukemia. Materials and Methods: An original, case-report study was performed. The diagnosis was confirmed by cytological, cytogenetic and molecular examinations of the peripheral blood and bone marrow at the comprehensive research cancer center— Institute of Oncology from Moldova. The real-time PCR was performed for quantitative detection of BCR-ABL gene p210 and p190 transcripts. The ECOG Scale and complete hematologic response (CR) estimated the short-term results. The ECOG performance status served as a measure of functional status. Its scores range from 0 to 5 and correlate with the level of patient functioning. CR is the disappearance of all detectable clinical and hematological signs of malignant neoplasm in response to treatment. CR span was assessed in months. The overall and relapse-free survivals asserted the long-term results of treatment, and were evaluated in months as a case. Results: CML may be manifested by life-threatening conditions, including infections and thrombotic events, splenic infarcts and ruptures, bleedings, etc. CML with the uncommon onset under the form of the ovarian apoplexy is described. The hematological CR was obtained under the treatment with imatinib mesylate. The molecular CR and the long-lasting overall survival (197.5 months) were achieved after the treatment with nilotinib. Under the treatment with tyrosine kinase inhibitors, the patient did not experience the disease burden and side effects, and resumed her work, with a good life quality (ECOG score is 0). Discussion: CML may be manifested by life-threatening health emergencies, especially thrombotic events, splenic infarcts and ruptures, bleedings, etc. The CML patients with high leukocyte and platelet counts may experience also different symptoms of hyperviscosity: tinnitus, priapism, stupor, visual abnormalities and cerebrovascular accidents. However, the management of CML with the life-threatening conditions, especially in the accelerated and acute phases, should be realized with participation of the multidisciplinary teams. Conclusions: The ovarian apoplexy may serve as a presenting feature of CML in young females with a highly elevated leukocyte count. The reported CML case underwent successful personalized management with 2 generations of tyrosine kinase inhibitors, even if designated with Socal intermediate-risk score and complicated by a health emergency.

Androgen receptor co-regulation in prostate cancer

Prostate cancer(PCa)progression relies on androgen receptor(AR)action.Preventing AR’s ligand-activation is the frontline treatment for metastatic PCa.Androgen deprivation therapy(ADT)that inhibits AR ligand-binding initially induces remission but eventually fails,mainly because of adaptive PCa responses that restore AR action.The vast majority of castration-resistant PCa(CRPC)continues to rely on AR activity.Novel therapeutic strategies are being explored that involve targeting other critical AR domains such as those that mediate its constitutively active transactivation function,its DNA binding ability,or its interaction with co-operating transcriptional regulators.Considerable molecular and clinical variability has been found in AR’s interaction with its ligands,DNA binding motifs,and its associated coregulators and transcription factors.Here,we review evidence that each of these levels of AR regulation can individually and differentially impact transcription by AR.In addition,we examine emerging insights suggesting that each can also impact the other,and that all three may collaborate to induce gene-specific AR target gene expression,likely via AR allosteric effects.For the purpose of this review,we refer to the modulating influence of these differential and/or interdependent contributions of ligands,cognate DNA-binding motifs and critical regulatory protein interactions on AR’s transcriptional output,which may influence the efficiency of the novel PCa therapeutic approaches under consideration,as co-regulation of AR activity.

A living cell-based fluorescent reporter for high-throughput screening of anti-tumor drugs

Suppression of cellular O-linkedβ-N-acetylglucosaminylation(O-Glc NAcylation)can repress proliferation and migration of various cancer cells,which opens a new avenue for cancer therapy.Based on the regulation of insulin gene transcription,we designed a cell-based fluorescent reporter capable of sensing cellular O-Glc NAcylation in HEK293 T cells.The fluorescent reporter mainly consists of a reporter(green fluorescent protein(GFP)),an internal reference(red fluorescent protein),and an operator(neuronal differentiation 1),which serves as a"sweet switch"to control GFP expression in response to cellular OGlc NAcylation changes.The fluorescent reporter can efficiently sense reduced levels of cellular OGlc NAcylation in several cell lines.Using the fluorescent reporter,we screened 120 natural products and obtained one compound,sesamin,which could markedly inhibit protein O-Glc NAcylation in He La and human colorectal carcinoma-116 cells and repress their migration in vitro.Altogether,the present study demonstrated the development of a novel strategy for anti-tumor drug screening,as well as for conducting gene transcription studies.

The Positive Effects of Proprietary Undenatured β-Glucans on Stressed Marine Life

The safety of beta-glucans, including undenatured beta-glucan (UDBG), has been exhaustively studied over the recent past and has shown to be safe and efficacious in rodents as well as in humans with less than optimal immune systems. As such, we sought to find the effect of UDBG on certainly stressed crustaceans and fish. The survival of shrimp larvae fed the UDBG and other diets was measured on day 16. The diet containing 11.7% UDBG reduced larvae mortality by 18%;which is almost twice as much as the mortality reduced by the MacroGard diet, and up to 19.5% less than a standard Commercial Diet. In an effort to understand how UDBG protects against stressed marine life, UDBG was given to LPS-challenged trout. The UDBG positively influenced the level of transcription of several genes relevant to the immune system and overall health of the trout. The experimental findings indicated that UDBG: 1) modifies inflammatory responses, 2) makes responses more flexible and versatile, 3) protects from cellular stress, and 4) enhances “effector” mechanisms. Importantly, there was no evidence of immune system over-activity.

Aging and Geriatric Dentistry

Five theories shed lights on the potential mechanisms of aging:somatic mutations,telomere loss,mitochondrial defects,and accumulation of altered proteins inside proteasomes.The existence of a program of aging is not yet identified,but overlaps with a program for risks of death.On the other hand,organisms are programmed for survival,which ultimately fails.This failure results in aging,notabily,focusing on alterations of specific genes.Irregular examinations,dysfunctions,insufficient use of fluoride,and removable partial dentures,are favoring the formation of caries and periodontal pathologies.Oral lesions are due to local trauma,related gingival recession,and formation of pockets.They are associated to insufficient removal of food/plaque.Epithelial thinning,and reduction of extracellular matrix components,lead to plications and foldings of the mucosal surface,and subsequently to bacterial colonization.Geriatric dentistry(or gerodontology)is an increasing field of dentistry,mostly associated with the growing percentage of patients over 80+years.

The novel C5 protein from tomato yellow leaf curl virus is a virulence factor and suppressor of gene silencing

Tomato yellow leaf curl virus(TYLCV)is known to encode 6 canonical viral proteins.Our recent study revealed that TYLCV also encodes some additional small proteins with potential virulence functions.The fifth ORF of TYLCV in the complementary sense,which we name C5,is evolutionarily conserved,but little is known about its expression and function during viral infection.Here,we confirmed the expression of the TYLCV C5 by analyzing the promoter activity of its upstream sequences and by detecting the C5 protein in infected cells by using a specific custom-made antibody.Ectopic expression of C5 using a potato virus X(PVX)vector resulted in severe mosaic symptoms and higher virus accumulation levels followed by a burst of reactive oxygen species(ROS)in Nicotiana benthamiana plants.C5 was able to effectively suppress local and systemic post-transcriptional gene silencing(PTGS)induced by single-stranded GFP but not double-stranded GFP,and reversed the transcriptional gene silencing(TGS)of GFP.Furthermore,the mutation of C5 in TYLCV inhibited viral replication and the development of disease symptoms in infected plants.Transgenic overexpression of C5 could complement the virulence of a TYLCV infectious clone encoding a dysfunctional C5.Collectively,this study reveals that TYLCV C5 is a pathogenicity determinant and RNA silencing suppressor,hence expanding our knowledge of the functional repertoire of the TYLCV proteome.

c-Jun, at the crossroad of the signaling network

c-Jun,the most extensively studied protein of the activator protein-1(AP-1)complex,is involved in numerous cell activities,such as proliferation,apoptosis,survival,tumorigenesis and tissue morphogenesis.Earlier studies focused on the structure and function have led to the identification of c-Jun as a basic leucine zipper(bZIP)transcription factor that acts as homo-or heterodimer,binding to DNA and regulating gene transcription.Later on,it was shown that extracellular signals can induce post-translational modifications of c-Jun,resulting in altered transcriptional activity and target gene expression.More recent work has uncovered multiple layers of a complex regulatory scheme in which c-Jun is able to crosstalk,amplify and integrate different signals for tissue development and disease.One example of such scheme is the autocrine amplification loop,in which signal-induced AP-1 activates the c-Jun gene promoter,while increased c-Jun expression feedbacks to potentiate AP-1 activity.Another example of such scheme,based on recent characterization of gene knockout mice,is that c-Jun integrates signals of several developmental pathways,including EGFR-ERK,EGFR-RhoA-ROCK,and activin B-MAP3K1-JNK for embryonic eyelid closure.After more than two decades of extensive research,c-Jun remains at the center stage of a molecular network with mysterious functional properties,some of which are yet to be discovered.In this article,we will provide a brief historical overview of studies on c-Jun regulation and function,and use eyelid development as an example to illustrate the complexity of c-Jun crosstalking with signaling pathways.

Adaptor protein APPL1 links neuronal activity to chromatin remodeling in cultured hippocampal neurons

Local signaling events at synapses or axon terminals are communicated to the nucleus to elicit transcriptional responses,and thereby translate information about the external environment into internal neuronal representations.This retrograde signaling is critical to dendritic growth,synapse development,and neuronal plasticity.Here,we demonstrate that neuronal activity induces retrograde translocation and nuclear accumulation of endosomal adaptor APPL1.Disrupting the interaction of APPL1 with Importin ocl abolishes nuclear accumulation of APPL1,which in turn decreases the levels of histone acetylation.We further demonstrate that retrograde translocation of APPL1 is required for the regulation of gene transcription and then maintenance of hippocampal late-phase long-term potentiation.Thus,these results illustrate an APPLl-mediated pathway that contributes to the modulation of synaptic plasticity via coupling neuronal activity with chromatin remodeling.

Multifunctions of Histone H1 Proteins

Among various histones, histone H1 proteins have been appreciated for their multiple functions in diverse biological processes. In addition to being a structural protein in chromatin, H1 proteins also play critical roles in cell cycle, gene expression, and development. Recent studies reveal the possible effects of H1 in some diseases, such as cancer and neurodegenerative diseases. Here, we review different variants of H1, the functions, and post translational modifications of H1 variants are also discussed.

Codimensional matrix pairing perspective of BYY harmony learning:hierarchy of bilinear systems,joint decomposition of data-covariance,and applications of network biology

One paper in a preceding issue of this journal has introduced the Bayesian Ying-Yang(BYY)harmony learning from a perspective of problem solving,parameter learning,and model selection.In a complementary role,the paper provides further insights from another perspective that a co-dimensional matrix pair(shortly co-dim matrix pair)forms a building unit and a hierarchy of such building units sets up the BYY system.The BYY harmony learning is re-examined via exploring the nature of a co-dim matrix pair,which leads to improved learning performance with refined model selection criteria and a modified mechanism that coordinates automatic model selection and sparse learning.Besides updating typical algorithms of factor analysis(FA),binary FA(BFA),binary matrix factorization(BMF),and nonnegative matrix factorization(NMF)to share such a mechanism,we are also led to(a)a new parametrization that embeds a de-noise nature to Gaussian mixture and local FA(LFA);(b)an alternative formulation of graph Laplacian based linear manifold learning;(c)a codecomposition of data and covariance for learning regularization and data integration;and(d)a co-dim matrix pair based generalization of temporal FA and state space model.Moreover,with help of a co-dim matrix pair in Hadamard product,we are led to a semi-supervised formation for regression analysis and a semi-blind learning formation for temporal FA and state space model.Furthermore,we address that these advances provide with new tools for network biology studies,including learning transcriptional regulatory,Protein-Protein Interaction network alignment,and network integration.

Nitrogen starvation induces genome-wide activation of transposable elements in Arabidopsis

Nitrogen(N)availability is a major limiting factor for plant growth and agricultural productivity.Although the gene regulation network in response to N starvation has been extensively studied,it remains unknown whether N starvation has an impact on the activity of transposable elements(TEs).Here,we report that TEs can be transcriptionally activated in Arabidopsis under N starvation conditions.Through genetic screening of idm1-14 suppressors,we cloned GLU1,which encodes a glutamate synthase that catalyzes the synthesis of glutamate in the primary N assimilation pathway.We found that glutamate synthase 1(GLU1)and its functional homologs GLU2 and glutamate transport 1(GLT1)are redundantly required for TE silencing,suggesting that N metabolism can regulate TE activity.Transcriptome and methylome analyses revealed that N starvation results in genome-wide TE activation without inducing obvious alteration of DNA methylation.Genetic analysis indicated that N starvationinduced TE activation is also independent of other well-established epigenetic mechanisms,including histone methylation and heterochromatin decondensation.Our results provide new insights into the regulation of TE activity under stressful environments in planta.